9250 • The Journal of Neuroscience, October 20, 2004 • 24(42):9250 –9260
Annual Meeting Symposium
Mechanisms and Roles of Axon–Schwann Cell Interactions
Gabriel Corfas,1,2 Miguel Omar Velardez,1,2 Chien-Ping Ko,3 Nancy Ratner,4 and Elior Peles5
Division of Neuroscience, Children’s Hospital, Boston, Massachusetts 02115, 2Department of Neurology, Harvard Medical School, Boston, Massachusetts
02115, 3Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520, 4Department of
Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229-7013, and 5Department of Molecular Cell
Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
1
Key words: neuregulin; erbB; node of Ranvier; NF1; perisynaptic; Schwann
Schwann cells (SCs) cover most of the surface of all axons in
peripheral nerves. Axons and these glial cells are not only in intimate physical contact but also in constant and dynamic communication, each one influencing and regulating the development,
function, and maintenance of the other. In recent years, there has
been significant progress in the understanding of the molecular
mechanisms of axon–Schwann cell interactions, particularly
those relevant for postnatal development and maintenance of
nerve function and structure. In this review, we discuss recent
progress in four aspects of axon–Schwann cell interactions, including the roles of the neuregulin1 (NRG1)– erbB signaling
pathway, the mechanisms underlying the formation and function
of the node of Ranvier, the role of perisynaptic Schwann cells at
the neuromuscular junction, and the mechanisms that generate
Schwann cell tumors.
Along the entire length of mammalian peripheral nerves, axons of motor, sensory, and autonomic neurons are in close association with SCs. The intimate contact between SCs and peripheral axons provided a first indication that these cells interact in
important ways. In the mature nervous system, Schwann cells can
be divided into four classes: myelinating cells (MSCs), nonmyelinating cells (NMSCs), perisynaptic Schwann cells (PSCs) (also
known as terminal Schwann cells), and satellite cells of peripheral
ganglia. These classes are based on their morphology, biochemical makeup, and the neuronal types (or area of their axons) with
which they associate. MSCs, the best characterized SC, wrap
around all large-diameter axons, including all motor neurons
and some sensory neurons. Each MSC associates with a single
axon and creates the myelin sheath necessary for saltatory nerve
conduction (Fig. 1 A). NMSCs associate with small-diameter axons of C-fibers emanating from many sensory and all postganglionic sympathetic neurons. Each NMSC wraps around several
sensory axons to form a Remak bundle, keeping individual axons
separated by thin extensions of the Schwann cell body (Fig. 1 B).
Received Sept. 3, 2004; revised Sept. 14, 2004; accepted Sept. 14, 2004.
This work was supported by National Institutes of Health Grants NS35884 (G.C.), DC04820 (G.C.), NS017954
(C.-P.K.), NS28840 (N.R.), and DAMD-17-02-1-0679 (N.R.). Support was also provided by the National Multiple
Sclerosis Society (N.R. and E.P.), the United States–Israel Binational Science Foundation (E.P.), and the Israel Science
Foundation (E.P.). We thank Samir Koirala and Kristine Roy for their critical reading of this manuscript, Alex Rosenbaum for the illustrations, and Carlos Rio, Yoshie Sugiura, and Zhihua Feng for micrographs.
Correspondence should be addressed to Dr. Gabriel Corfas, Division of Neuroscience, Children’s Hospital, 300
Longwood Avenue, Boston, MA 02115. E-mail: [email protected].
DOI:10.1523/JNEUROSCI.3649-04.2004
Copyright © 2004 Society for Neuroscience 0270-6474/04/249250-11$15.00/0
Finally, located more peripherally, PSCs reside at the neuromuscular junctions (NMJ), where they cover, without completely
wrapping around, the presynaptic terminal of motor axons (Fig.
1C). Satellite cells, which will not be discussed here, associate with
neuronal cell bodies in peripheral ganglia.
Schwann cells, their origins, and their adult characteristics
The diverse types of SCs found in the adult nerve are primarily
derived from a single precursor cell type, the neural crest cell.
Some SCs may derive from placodes and ventral neural tube. The
multipotent and actively migratory neural crest cells migrate into
the peripheral nerves during embryonic development, in which
they mature in a stepwise process, giving rise to all SCs (Fig. 2). By
embryonic day 12 (E12) to E13 in mice, Schwann cell precursors
begin to express three differentiation markers: P0 (myelin protein 0), GAP43 (growth-associated protein 43), and F-spondin,
(Jessen and Mirsky, 1999). From E15 to the time of birth, these
precursors give rise to immature Schwann cells, which express
S100␤ and low levels of the myelin protein P0 (Jessen et al., 1994).
Finally, after birth, the immature SCs differentiate into myelinating, nonmyelinating, and perisynaptic phenotypes, a process that
continues over several weeks. Axons provide signals that regulate
the choice between the different SC phenotypes, but molecular
identity of these signals remains unknown. Undoubtedly, signals
from the different axonal types and regions are important.
The three types of SCs not only differ in the type of axons with
which they associate, their location along axons, and their morphology, but they also differ dramatically in their biochemical
composition. MSCs, the best characterized biochemically, express myelin proteins such as MBP (myelin basic protein),
PMP22 (peripheral myelin protein 22), P0, MAG (myelinassociated glycoprotein), and MAL (myelin and lymphocyte protein). These proteins are critical for the formation and function of
myelin sheaths. The NMSCs and PSCs have been characterized to
a much lesser extent. NMSCs can be distinguished from their
neighboring MSCs by their high levels of glial fibrillary acidic
protein (GFAP) (Jessen et al., 1990), the low-affinity neurotrophin receptor p75 (Jessen et al., 1990) and the cell adhesion molecule L1 (Faissner et al., 1984). No specific markers exist for PSCs,
but, within the NMJ, these cells can be easily visualized and studied using S100␤ as a marker (Woolf et al., 1992) (see Fig. 4).
Myelinating, nonmyelinating, and perisynaptic SCs also differ
in their function. As with their other aspects, MSCs are the best
understood. These cells form the myelin sheath critical for rapid
Corfas et al. • Axon–Schwann Cell Interactions
J. Neurosci., October 20, 2004 • 24(42):9250 –9260 • 9251
Figure 1. Myelinated, unmyelinated, and perisynaptic Schwann cells as seen with the electron microscope. A, Cross section of
a myelinated axon of an adult mouse sciatic nerve. The myelin sheath (MS) surrounding the axon (Ax) and the Schwann cell nucleus
(S) are clearly visible. B, Cross section of a bundle of unmyelinated axons of an adult mouse sciatic nerve. The Schwann cell forms
the Remak bundle, a bouquet-like bundle of thin axons, each separated from its neighbor by thin cytoplasmic extensions of the
Schwann cell. C, Cross section of a frog neuromuscular junction reveals three juxtaposed cellular elements: the perisynaptic
Schwann cell, nerve terminal (N), and muscle fiber (M). The perisynaptic Schwann cell body (S indicates nucleus) and its processes
cap the nerve terminal, but the processes do not wrap around the nerve terminal region facing acetylcholine receptors on muscle.
mice. The first series of mice lacking
NRG1, erbB2, or erbB3 established the essential role of these molecules in Schwann
cell precursor development (Lee et al.,
1995; Meyer and Birchmeier, 1995; Erickson et al., 1997; Riethmacher et al., 1997).
These mice have cranial ganglia defects, as
well as reduction of Schwann cells, enteric
ganglia, and adrenal chromaffin cells, suggesting that the primary site of action for
NRG1– erbB signaling is neural crest cells
(Erickson et al., 1997; Riethmacher et al.,
1997; Lin et al., 2000). Unfortunately, these
mutant mice die as embryos because of heart
defects; thus, these initial studies were limited to early stages of development.
Subsequently, NRG1– erbB signaling
in axon–SC interactions were examined
using more elaborated animal models, including knock-outs of specific NRG1 iso-
saltatory nerve conduction. They also regulate the formation and
contribute to the structure of the nodes of Ranvier (see below).
MSCs influence several aspects of axonal structure, including axonal diameter, axonal neurofilament spacing, and phosphorylation (Hsieh et al., 1994). In contrast, the functional roles of
NMSCs have been very poorly investigated, but recent studies
indicate that they play critical roles in the maintenance and function of unmyelinated axons and nociception in the adult (see
below). PSCs in amphibians and mammals appear to play important roles in the maturation and function of the NMJ, as well as in
its regeneration after injury (see below).
NRG1– erbB signaling in axon–Schwann cell interactions
Numerous molecules mediate specific aspects of the interactions
between peripheral axons and SCs, including MAG (Yin et al.,
1998), p75 (Cosgaya et al., 2002), IGF1 (Syroid et al., 1999), integrins (Feltri et al., 2002), and TGF-␤ (Guenard et al., 1995). The
growth factor NRG1 and its receptors, the erbB receptors tyrosine
kinases, have emerged as key regulators of axon–SC interactions
at every stage and for all SC types. NRG1 is also known as glial
growth factor, a protein purified as a mitogen for Schwann cells
in culture (Marchionni et al., 1993). Early studies showed that
spinal cord motoneurons, DRG sensory neurons, and autonomic
neurons express NRG1 (Corfas et al., 1995) and that SCs express
erbB2 and erbB3 receptors (Meyer and Birchmeier, 1995). Thus,
it seemed reasonable that this ligand–receptor system would mediate interactions between these neurons and SCs. Indeed, many
in vitro studies provided compelling evidence that NRG1 regulates many aspects of SC development. NRG1 can induce the
differentiation of neural crest cells into the SC phenotype (Shah
et al., 1994), the maturation of SC precursors isolated from embryonic nerves (Dong et al., 1995), and the survival of SCs isolated from neonate nerves (Syroid et al., 1996). NRG1 also promotes SC motility and migration (Mahanthappa et al., 1996) and
induces SC proliferation in culture (Marchionni et al., 1993).
NRG1 appears to also regulate physiological properties of SCs
because it induces expression of Na ⫹ channels (Wilson and Chiu,
1993) and increases gap junction communication between SCs
(Chandross et al., 1996).
The importance of NRG1– erbB signaling in SC development
has also been demonstrated in vivo with genetically modified
Figure 2. NRG1– erbB signaling and Schwann cell development. During development, neural crest cells give rise to Schwann cell precursors, which then develop into the three adult
phenotypes: PSCs, NMSCs, or MSCs. Whereas, during their differentiation into MSCs and NMSCs,
the precursors proceed through a stage called immature Schwann cell, the direct precursor of
PSCs remains unknown. NRG1– erbB signaling regulates important aspects of Schwann cell
biology at each step of their development (see boxed text).
9252 • J. Neurosci., October 20, 2004 • 24(42):9250 –9260
forms (Kramer et al., 1996; Meyer et al., 1997; Wolpowitz et al.,
2000) and rescue of early lethality by expression of erbB receptors
in the heart (Morris et al., 1999; Woldeyesus et al., 1999). Altogether, these studies showed that (1) different NRG1 isoforms
have similar yet somewhat different roles in SC development, (2)
defects in SC development attributable to lack of NRG1– erbB
signaling in embryogenesis result in the degeneration of both
sensory and motor neurons in mice and (3) defects in NRG1–
erbB signaling during embryonic development lead to NMJ defects. These studies highlighted the importance of SCs in the development and maintenance of peripheral nerves.
More recently, several studies have explored NRG1– erbB signaling in axon–SC interactions with conditional knock-outs
(Garratt et al., 2000), mice heterozygous for NRG, erbB2, and
erbB3 (Michailov et al., 2004), and cell-specific blockade or erbB
receptors in transgenic mice (Chen et al., 2003). These studies
showed that the roles of erbB signaling in SCs differ between
postnatal and embryonic cells, as well as between myelinating
and nonmyelinating Schwann cells.
To interfere with NRG1– erbB signaling between unmyelinated axons and NMSCs, Chen et al. (2003) generated transgenic
mice expressing a dominant-negative erbB receptor in NMSCs.
These mice had normal peripheral nerves until the third postnatal week but then developed a small fiber neuropathy with loss of
thermal nociception, consistent with dysfunction of unmyelinated C-fiber axons. The loss of erbB signaling in NMSCs resulted in the loss of Remak bundles and extensive proliferation of
NMSCs. These results were surprising, because they indicated
that, in adult NMSCs, erbB signaling prevents rather than induces proliferation, opposite to its role during development. The
rate of SC apoptosis was also increased in these mice, demonstrating that erbB signaling is a pro-survival stimulus for adult
NMSCs. The mutant mice had significant loss of unmyelinated
axons by postnatal day 30, indicating that NMSC are involved in
maintenance of unmyelinated axon integrity throughout life. Interestingly, even at stages in which mice were unable to respond
to thermal stimuli, they still retained 50% of their C-fiber axons,
suggesting that NMSCs may play a role in electrical conduction of
unmyelinated axons as MSCs do for myelinated axons. At later
stages, the number of unmyelinated DRG neurons was dramatically reduced, indicating that NMSCs are involved in the promotion of long-term sensory neurons survival. This DRG loss occurred in conjunction with a dramatic reduction in the levels of
expression of glial cell line-derived neurotrophic factor, a trophic
factor expressed by SCs and known to be important for the survival of a population of C-fiber neurons. These results show that,
as part of a set of reciprocal axon–SC interactions, adult NMSCs
are important in the maintenance of C-fiber sensory neurons as a
source of essential trophic support.
The roles of NRG1– erbB signaling in MSCs were first studied
by Garratt et al. (2000). They generated mice in which the erbB2
gene was deleted by expression of Cre recombinase under the
control of the promoter of Krox20, a transcription factor expressed by MSCs. These mice showed hypomyelination of peripheral nerves, revealing that erbB signaling is necessary for normal myelination. Moreover, at early postnatal stages, there was a
significant reduction in the number of developing SCs in the
ventral and dorsal roots, suggesting that erbB signaling also regulates the SC precursor pool. Interestingly, adult nerves contained normal numbers of SCs, leading the authors to suggest
that other mechanisms compensated for the lack of erbB signaling. This line of inquiry was taken a step further by Michailov et
al. (2004). Their study showed that mice with only one copy of the
Corfas et al. • Axon–Schwann Cell Interactions
NRG1 gene have thinner myelin, whereas mice overexpressing
one of the NRG1 isoforms (type III NRG1) in neurons under the
control of the Thy1.2 promoter have thicker myelin. Interestingly, type I NRG1 did not have the same effect. Because NRG1
heterozygotes showed the same phenotype as observed in nrg1:
erbb2:erbb3 triple heterozygotes, the authors concluded that axonal NRG is the rate-limiting factor for myelination. This study
also found normal internodal length in the mutant mice, suggesting that NRG1– erbB signaling is not involved in the regulation of
SC length. This surprising result suggested that the regulation of
myelin thickness and internode length might be regulated by
different mechanisms. However, this may have resulted from an
incomplete blockade of erbB signaling in these mice.
NRG1– erbB signaling appears also to regulate important aspects of PSC biology. Trachtenberg and Thompson (1996) found
that, in the neonate, PSCs die after muscle denervation and that
this apoptosis could be prevented by application of NRG1. Furthermore, exogenous NRG1 applied to normal neonatal muscles
resulted in retraction of nerve terminals and alterations in PSC
morphology (Trachtenberg and Thompson, 1997). Because both
SCs and muscle have erbB receptors, it is not clear which cell is the
primary target of NRG1, but the investigators speculated that
NRG1 acted on PSCs.
These studies provide irrefutable support for the essential
roles of NRG1– erbB signaling in axon–SC interactions during
development and in the adult. Nevertheless, many important
questions remain to be answered regarding the mechanisms by
which NRG1– erbB signaling regulates SC biology, including how
signaling through the same erbB receptors can result in different
biological outcomes in SCs depending on the NRG1 isoform used
or the state of differentiation of the glia.
Axoglial interactions at the node of Ranvier
As discussed above, myelin is essential for efficient and rapid
propagation of action potentials. However, this function also depends on the molecular specialization of the nodes of Ranvier, the
short periodical interruptions in the myelin sheath that are regularly spaced at intervals of ⬃100 times the axonal diameter. The
nodal region is organized into several distinct domains, nodes,
paranodes, and juxtaparanodal region (Fig. 3). Each domain contains a unique set of ion channels, cell adhesion molecules, and
cytoplasmic adaptor proteins (Poliak and Peles, 2003; Salzer,
2003). Disruption in nodal organization results in pathophysiological changes often seen in demyelinating diseases. The local
differentiation of myelinated axons is tightly regulated by MSCs
through contact-dependent mechanisms.
The nodal axolemma is characterized by high density (⬎1200/
mm 2) of Na ⫹ channels essential for the generation of the action
potential during saltatory conduction. Na ⫹ channels colocalize
with KCNQ2 K ⫹ channels (Devaux et al., 2004) and several other
transmembrane and cytoskeletal proteins. These include the cell
adhesion molecules of the Ig superfamily (Ig-CAMs) NrCAM
and neurofascin 186 (NF186) (Davis et al., 1996), the cytoskeletal
adaptor ankyrin G (Kordeli et al., 1995), and the actin-binding
protein spectrin ␤IV (Berghs et al., 2000). Axoglial contact at the
nodes can be mediated by both the nodal CAMs and the ␤ subunit of Na ⫹ channel (Isom, 2002). Ankyrin G, a membranecytoskeleton adaptor that links integral membrane proteins to
the spectrin cytoskeleton, interacts with Na ⫹ channels (Srinivasan et al., 1988), KCNQ2 (Devaux et al., 2004), NF186 and NrCAM (Garver et al., 1997), as well as to ␤IV spectrin, a spectrin
isoform that is enriched at the nodes of Ranvier and axon initial
segments (Berghs et al., 2000). The interaction between ankyrin
Corfas et al. • Axon–Schwann Cell Interactions
J. Neurosci., October 20, 2004 • 24(42):9250 –9260 • 9253
(Tait et al., 2000). Although NF155 binds
directly to contactin, it is presently unclear
whether the Caspr– contactin complex interacts directly with NF155 (Charles et al.,
2002; Gollan et al., 2003). Both Caspr and
contactin are essential for the formation of
the paranodal junction, and, in their absence, the ultrastructure of the paranodes
is severely altered. Specifically, the gap between glial and axonal membranes is increased, and the electron-dense material
forming the septa that are the hallmark of
the PNJ in wild-type mice is absent (Bhat
et al., 2001; Boyle et al., 2001; Gollan et al.,
2003). Similar to other so-called paranodal mutants (Poliak and Peles, 2003),
such as the galactolipids (Dupree et al.,
1999; Poliak et al., 2001) and sulfatideFigure 3. Molecular structure of the node of Ranvier. Longitudinal section through the nodal region of a peripheral myelinated deficient mice (Ishibashi et al., 2002), the
axon showing the organization and composition of axonal and glial domains. The axon is covered by an MSC, which in turn is absence of a normal paranodal junction
surrounded by a basal lamina. In the paranodal region, the myelin sheath forms a series of paranodal loops (PNL) that invaginate results in only a minor expansion of the
and appose the axon creating a septate-like structure. At the node, the outermost cytoplasmic extension of MSC contains numernodes but causes a shift in the accumulaous microvilli that contact the axolemma. Specific sets of proteins are enriched in each domain of both axon (red text) and Schwann
tion of K ⫹ channels from the juxtaparancells (blue text).
odal region to the paranodes (Bhat et al.,
2001; Boyle et al., 2001; Gollan et al.,
G and ␤IV spectrin may provide further anchorage of the nodal
2003). Thus, an important function of these junctions is to form
Na ⫹ channel and Ig-CAMs to the axonal cytoskeleton. The nodal
a barrier between the nodal Na ⫹ channels and the juxtaparanaxolemma is contacted by microvilli emanating from the outer
odal K ⫹ channels.
The juxtaparanodal region is located beneath the compact
aspect of MSCs. Three ERM proteins ezrin, radixin, and moesin,
myelin at both sides of each internodal interval. It is characterized
as well as ezrin-binding protein EBP50 and Rho-A GTPase, are
by the presence of delayed rectifier K ⫹ channels of the Shaker
localized at the microvilli (Melendez-Vasquez et al., 2001;
family, Kv1.1, Kv1.2, and their Kv␤2 subunit, that may stabilize
Scherer et al., 2001). Several extracellular matrix proteins are
conduction and help to maintain the internodal resting potential
present in the nodal gap under the basal lamina, including the
(Wang et al., 1993; Vabnick et al., 1999). At this site, the channels
hyaluronan-binding proteoglycan versican (Apostolski et al.,
colocalize and create a complex with Caspr2, the second member
1994), tenascin C (Rieger et al., 1986; Martini et al., 1990), and
of a family of putative cell recognition molecules (Poliak et al.,
syndecans (Goutebroze et al., 2003). Dystroglycan is also located
1999). Two other proteins that are found at the juxtaparanodal
at the nodes (Saito et al., 2003). SC-specific ablation of dystroglyregion are TAG-1 (transient axonal glycoprotein 1), a GPIcan results in disorganization of the microvilli, marked reduction
anchored cell adhesion molecule related to contactin (Traka et
in nodal Na ⫹ channels, and consequently impaired nerve conduction (Saito et al., 2003).
al., 2002), and connexin 29, which is found at the glial membrane
The paranodal junctions (PNJ) that are formed between the
(Altevogt et al., 2002). Axonal Caspr2 creates a cis-complex with
axon and the myelinating cell flank the nodes of Ranvier. In this
TAG-1 that associates with a glial-derived TAG-1. In the absence
region, the compact myelin lamellae open up into a series of
of Caspr2 or TAG-1, K ⫹ channels do not accumulate at the juxtaparanodal region, and, instead, they are distributed along the
cytoplasmic loops that spiral around the axon, forming a series of
internodes, suggesting that Caspr2 and TAG-1 form a scaffold
septate-like junctions with the axolemma. These junctions apthat maintains K ⫹ channels at their correct juxtaparanodal posipear relatively late during myelination, first generated closer to
tion (Poliak et al., 2003; Traka et al., 2003).
the nodes by the most outer paranodal loop and then forming
During the development of myelinated nerves, the different
gradually as additional loops are attached to the axon. As a result,
nodal domains are formed gradually. Na ⫹ channels are first clusthey are composed of a number of rings that represent each turn
tered at the nodes, followed by the generation of the paranodal
of the myelin wrap. The PNJ was proposed to provide attachment
junction, and only then by the clustering of K ⫹ channels at the
of the myelin sheath to the axon, to separate the electrical activity
juxtaparanodal region (Vabnick et al., 1996, 1999). Na ⫹ channels
at the node of Ranvier from the internodal region under the
cluster initially at sites adjacent to the edges of processes extended
compact myelin sheath, and to serve as a boundary that limits the
by MSCs (Vabnick et al., 1996; Ching et al., 1999). Additional
lateral diffusion of membrane components. The axonal memlongitudinal growth of these glial cell processes is associated with
brane at the paranodes contains a complex of cell adhesion molthe movement of Na ⫹ channel clusters until ultimately two
ecules that include Caspr (Einheber et al., 1997; Peles et al., 1997)
neighboring clusters appear to fuse, indicating that these chan[contactin-associated protein, also known as paranodin (Menenels are positioned by direct glial cell contact (Pedraza et al.,
goz et al., 1997)] and the glycosylphosphatidylinositol (GPI)2001). In sciatic nerve, NrCAM, NF186, and ankyrin G precede
linked cell adhesion molecule contactin (Rios et al., 2000). This
Na ⫹ channels, suggesting that these cell adhesion molecules bind
complex is connected to the axonal cytoskeleton through protein
ankyrin G, which in turns recruits Na ⫹ channels (Lambert et al.,
4.1B (Gollan et al., 2002). The glial membrane at the PNJ contains
1997; Jenkins and Bennett, 2002). In support of this model, the
neurofascin 155 (NF155), a spliced isoform of the cell adhesion
addition of a soluble NrCAM to myelinating dorsal root ganglia
molecule neurofascin that is specifically found at the glial loops
9254 • J. Neurosci., October 20, 2004 • 24(42):9250 –9260
Corfas et al. • Axon–Schwann Cell Interactions
cultures was shown to inhibit Na ⫹ clustering (Lustig et al., 2001).
Moreover, the appearance of ankyrin G and Na ⫹ channels at the
nodes is delayed in NrCAM null mice (Custer et al., 2003), indicating that this adhesion molecule participates in the clustering of
these channels. Cell– cell contact controls the two other domains
near the nodes; the formation of the paranodes requires Caspr
and contactin (Bhat et al., 2001; Boyle et al., 2001; Gollan et al.,
2003), whereas the formation of the juxtaparanodal region depends on the presence of Caspr2 and the contactin-related molecule TAG-1 (Poliak et al., 2003; Traka et al., 2003).
In summary, several proteins that may mediate the interactions between myelinating Schwann cells and their underlying
axons have been identified, and their role in the local differentiation of the nodal region is being explored. However, despite this
progress, the exact molecular mechanisms by which myelinating
glial cells control the formation of the nodes and, particularly, the
clustering of Na ⫹ channels should probably await the identification of novel components in the future.
Perisynaptic Schwann cells in neuromuscular junction
development and maintenance
PSCs cap the presynaptic motor nerve terminal, which in turn
aligns with postsynaptic acetylcholine receptors (AChRs) at vertebrate NMJs (Fig. 1). The arrangement of these three intimately
juxtaposed cellular elements was demonstrated by electron microscopy more than four decades ago (Birks et al., 1960), but it
was not until the 1990s that it became clear that PSCs play active
roles in synaptic function, growth, and maintenance. One key
finding was the profuse sprouting of PSC processes observed after
nerve injury at the mammalian NMJs (Reynolds and Woolf,
1992). The significance of this observation was soon recognized
and extended by Thompson and colleagues, who demonstrated
that PSC sprouts may lead nerve terminal growth during synaptic
regeneration and sprouting (Son and Thompson, 1995). Using
repeated in vivo imaging, Ko and colleagues have shown that PSC
processes are dynamic and may also lead nerve terminal sprouts
during synaptic remodeling at frog NMJs (Chen et al., 1991; Chen
and Ko, 1994; Ko and Chen, 1996). PSCs have also been shown to
sense synaptic activity by raising their intracellular calcium
(Jahromi et al., 1992; Reist and Smith, 1992) and to be capable of
modulating synaptic transmission at the NMJ in response to manipulation of G-protein pathways or internal calcium levels (Robitaille, 1998; Castonguay and Robitaille, 2001). Coincidentally,
the role of glial cells in synaptic function and development in the
CNS also began to unfold in the 1990s (Newman and Volterra,
2004). The importance of glial cells as active and integral components of chemical synapse has now been well acknowledged and
has led to the concept of the tripartite synapse (Araque et al.,
1999).
The frog NMJ has served as an excellent model to investigate
the roles of PSCs. Two vital probes, peanut agglutinin (PNA),
which labels the extracellular matrix associated with frog PSCs
(Ko, 1987), and a monoclonal antibody (mAb), 2A12, which labels the external membrane surface of frog PSCs (Astrow et al.,
1998), provide powerful tools for the study of PSC behavior at
adult and developing NMJs in vivo (Fig. 4). In addition, mAb
2A12 can be used with complement-mediated lysis to selectively
ablate PSCs en masse from frog muscles (Reddy et al., 2003).
Nerve–muscle contacts can be formed in the absence of
Schwann cells in tissue culture (Kullberg et al., 1977), and transient nerve–muscle contacts have also been seen in mouse mutants that lack of Schwann cells (Riethmacher et al., 1997; Morris
et al., 1999; Lin et al., 2000; Wolpowitz et al., 2000). Thus, it
Figure 4. Perisynaptic Schwann cells at the neuromuscular junction. Frog skeletal muscle
triple labeled with anti-neurofilament for axons (first panel, arrow) and synapsin I antibodies
for nerve terminals (first panel, arrowhead), a monoclonal antibody, 2A12, for perisynaptic
Schwann cells (second panel, the cell bodies are marked with *), and ␣-bungarotoxin for
postsynaptic acetylcholine receptors (third panel). The merged image is shown in the fourth
panel.
appears that the initial formation of nerve–muscle contact does
not require PSCs. However, PSCs are present and dynamic soon
after the initial NMJ formation. During tadpole development,
PSCs partially colocalize with developing nerve terminals at the
earliest discernible NMJs but quickly cover the full extent of
NMJs and often extend profuse processes beyond the nerve terminals by tens or hundreds of micrometers. Repeated, in vivo
observations of identified tadpole NMJs show that developing
nerve terminals grow along these PSC sprouts in tadpoles (Reddy
et al., 2003). When PSC were specifically ablated, very few NMJs
showed nerve terminal growth and nearly one-half underwent
retraction, in contrast to control muscles, which showed robust
NMJ growth. Furthermore, whereas ⬃10% of NMJs observed in
controls were new synapses, no new synapses were seen in PSCablated muscles. These results demonstrate that PSCs promote
synaptic growth and are vital for the stability of developing NMJs
in vivo.
The mechanisms by which SCs contribute to neuromuscular
synaptogenesis are not completely understood. In cultures con-
Corfas et al. • Axon–Schwann Cell Interactions
taining embryonic Xenopus spinal neurons and muscle, neurotrophic factors and elevated cAMP induce a dramatic increase in
neuron survival and neurite outgrowth (Peng et al., 2003). However, the number of nerve–muscle contacts that showed AChR
clusters was greatly inhibited. Interestingly, addition of medium
conditioned by SCs or TGF-␤1 increased AChR clusters at neuron–muscle contacts (Peng et al., 2003; Feng and Ko, 2004).
These findings suggested that Schwann cell-derived factors allow
neurons to switch from a “growth phase” to a “synaptogenic
phase.” In addition, SC-conditioned medium modulates transmitter release at the nerve–muscle contacts in Xenopus culture, by
increasing the frequency but not the amplitude of spontaneous
synaptic current. The identity of the factors that promote these
effects is not known, but they appear to be small molecules of ⬍5
kDa (Cao and Ko, 2001).
PSC ablation has provided an effective tool to selectively
“knock-out” PSCs and thus investigate the roles of these cells in
the maintenance and function of adult NMJs in vivo (Reddy et al.,
2003). After acute PSC ablation (up to 5 hr after ablation), no
abnormality of nerve terminal morphology or clusters of AChRs
was reported at the light microscopic level. Despite the damage of
PSCs, the ultrastructure of nerve terminals and muscles was unchanged, suggesting that acute ablation of PSCs does not alter
synaptic structure. Moreover, miniature endplate potentials
(mepps), evoked endplate potentials (epps), quantal contents,
and paired-pulse facilitation and synaptic depression in response
to high-frequency stimulation before and after acute PSC ablation were unchanged. Furthermore, acute ablation of PSCs did
not affect muscle twitch tension in response to nerve stimulation.
All in all, these findings suggest that PSCs, despite their capability
to modulate transmitter release in response to pharmacological
manipulations (Auld et al., 2003), do not seem to play a significant role in acute synaptic modulation and the overall functioning of adult muscles.
In contrast, PSCs are essential for the long-term maintenance
of synaptic structure and function (Reddy et al., 2003). One week
after PSC ablation, the frequency of mepps, the amplitude of
epps, and the mean quantal content were reduced approximately
by half, whereas mepp size was not altered. Nerve-induced muscle twitch tension was significantly reduced 1 week after PSC
removal. These changes in presynaptic function were accompanied by partial or total retraction of nerve terminals, as seen with
light microscopy. Electron microscopy showed “empty” synaptic
gutters resulting from the retraction of nerve terminals. However, there were no signs of either nerve damage typically seen
after axotomy or detachment of the remaining length of the retracting nerve terminals. Thus, it seems that, rather than acting as
a “glue” to mechanically attach nerve terminals, the PSCs and
their derived factors maintain synaptic structure and function.
The identity of these factors remains to be investigated.
Repeated in vivo imaging of double-labeled NMJs has shown
that, in contrast to mammals, frog PSC sprouting after axotomy
occurs with the arrival of regenerating nerve terminals. PSCs extend processes ahead of regenerating nerve terminals, which
grow along the preceding PSC processes (Koirala et al., 2000).
These observations suggest that regenerating nerve terminals induce PSCs sprouting, and PSC sprouts, in turn, lead and guide
nerve terminal sprouts. Similar roles for PSCs in leading growing
nerve terminals during synaptic remodeling (Chen et al., 1991;
Macleod et al., 2001) and during sprouting induced by nerve
implants (Chen and Ko, 1994; Ko and Chen, 1996) have been
reported. In addition to a guiding role, in the frog, SCs may also
play a role in the aggregation of AChRs at extrajunctional sites
J. Neurosci., October 20, 2004 • 24(42):9250 –9260 • 9255
during nerve reinnervation and sprouting by expressing active
isoforms of agrin (Yang et al., 2001).
Evidence for PSCs sprouts leading regenerating nerve terminals in vivo has also been made in mammalian muscles (O’Malley
et al., 1999; Kang et al., 2003). These in vivo observations have
confirmed previous suggestions inferred from static images that
regenerating axons indeed grow along PSC sprouts at mammalian NMJs. Together, in vivo imaging studies suggest that PSCs
guide and lead the growth of regenerating and sprouting nerve
terminals at adult vertebrate NMJs. Whether PSCs are absolutely
required for guiding nerve terminal sprouting at adult NMJs is
not clear. This question could be answered by ablating PSCs at
regenerating NMJs.
In summary, studies from the past decade have revealed many
active and essential roles of PSCs in synaptic function, formation,
and maintenance throughout the life of vertebrate NMJs (for
review, see Auld et al., 2003; Kang et al., 2003; Koirala et al., 2003).
These studies suggest that PSCs, similar to CNS glial cells (for
review, see Ullian et al., 2004), may instruct neurons to make
larger, stronger, and more stable synapses. However, little is
know about the identity of the molecules that PSCs and nerve
terminals communicate with each other at the NMJ. To have a
complete understanding of the tripartite neuromuscular synapse,
the future challenge is to unravel the molecular mechanisms of
the reciprocal interactions among PSCs, nerve terminals, and
muscles.
Schwann cell tumors
As described above, communication between axons and SCs is
critical for normal nerve function, and disruption of the intimate
interactions of SCs with axons results in debilitating peripheral
neuropathies, including those caused by peripheral nerve tumors. These tumors can be classified as neurofibromas and
schwannomas. Neurofibromas are unencapsulated benign tumors that contain Schwann cells, mast cells, fibroblasts, and perineurial cells comingled with axons in an abundance of collagenrich matrix. Schwann cells account for 60 – 80% of the cells in
neurofibromas, as defined by staining for the S100␤ protein (Stefansson et al., 1982; Peltonen et al., 1988). In contrast, schwannomas are encapsulated benign tumors almost entirely composed of Schwann cells that are perched on, but not comingled
with, normal nerve bundles (Fig. 5). Neurofibromas occasionally
progress to malignant peripheral nerve sheath tumors (MPNST)
(Evans et al., 2002), whereas schwannomas apparently do so only
after radiation exposure. Schwannomas consist almost entirely of
S100␤-positive cells (Johnson et al., 1988). At the electron microscopic level, interdigitating SC processes are frequent, and
schwannoma cells have characteristic SC basal lamina (Cravioto,
1969; Erlandson and Woodruff, 1982). Schwann cells within the
tumor are surrounded by a collagen-poor, laminin-rich matrix.
Clues to tumor formation come from inherited human diseases in which affected individuals are predisposed to develop SC
tumors. Neurofibromatosis type 1 (NF1) and neurofibromatosis
type 2 (NF2) arise from mutations in different genes, each of
which plays a key role in regulating SC function. The Nf1 gene on
human chromosome 17 encodes an intracellular signaling molecule that functions as a GTPase activating protein for Ras proteins, whereas the Nf2 gene on human chromosome 22 encodes a
cytoskeletal-membrane linking protein. Patients with NF1 and
NF2 typically present with different types of benign SC tumors in
which most SCs lose contact with axons. Neurofibromas are the
hallmark of NF1 disease, whereas schwannomas are the hallmark
of NF2 disease (Fig. 5). There is great interest in neurofibroma-
9256 • J. Neurosci., October 20, 2004 • 24(42):9250 –9260
Corfas et al. • Axon–Schwann Cell Interactions
tosis type 1 because it is one of the most
common of all inherited human diseases,
affecting 1 in 2500 –3500 individuals of all
races worldwide (Rasmussen and Friedman, 2000). The prevalence of NF1 is similar to all the Charcot-Marie-Tooth peripheral neuropathies together (1:2000).
NF1 is inherited as a dominant trait. It
is a complex disease with an unpredictable
clinical course. Diagnostic criteria, two or
more of which define a diagnosis of NF1,
include the following: cafe-au-lait macules, freckling, optic glioma, Lisch nodules, a bony lesion, a first degree relative
with NF1, and two or more benign nerve
sheath tumors (neurofibromas) (Gutmann et al., 1997). Numerous abnormal- Figure 5. Schwann cell tumors. In neurofibromas, Schwann cells fibroblasts and perineurial cells are within collagen-rich tumor
ities can be observed in individual NF1 pa- matrix; axons and mast cells are common. Neurofibromas are not encapsulated, although the plexiform neurofibroma develops
tients. At least one-half of NF1 children inside the perineurium (not shown). Schwannomas are encapsulated by a collagenous sheath and are made up almost entirely of
have learning disabilities (for review, see S100␤-positive Schwann cells, with little or no fibroblast involvement; axons are present only at the boundary of the tumor with
Kayl and Moore, 2000). Short stature, the associated nerve trunk.
macrocephaly, benign pilocytic astrocyto(Kim et al., 1995). Some Nf1 phenotypes are likely caused by
mas, and scoliosis are also frequent (Friedman and Birch, 1997).
increased Ras-GTP because morphological changes and deThe 350 kb Nf1 gene on human chromosome 17q11.2 is a
creased cell division in Nf1 mutant SCs are mimicked in SCs
tumor suppressor gene, and complete loss is correlated with tuexpressing a constitutively activated Ha-Ras allele (Ridley et al.,
mor formation (Legius et al., 1993). NF1 disease is thought to be
1988; Kim et al., 1995). In addition, farnesyl protein transferase
caused by loss of NF1 protein because defined Nf1 mutations
inhibitor, a drug that inhibits H-Ras activity, reverses proliferapredict deletions and rearrangements with no evidence for
tion abnormalities in mouse SCs lacking Nf1 (Kim et al., 1997).
dominant-negative effects; mutations are found scattered
Neurofibromin also has ill-defined, non-Ras-related functhroughout the gene (Fahsold et al., 2000). No relationship betions. Mutation in Drosophila Nf1 results in small sluggish flies
tween genotype and phenotype has been defined except for pawith a block in PACAP (pituitary adenylate cyclase-activating
tients with gross gene deletions who may have deletions in
polypeptide)-stimulated enhancement of inwardly rectifying K ⫹
gene(s) contiguous to Nf1. These individuals have a severe NF1
channels at the larval body wall NMJ (Guo et al., 1997). This is not
phenotype, with large neurofibroma burden (Lopez-Correa et
an effect of the classical Ras–MAPK (mitogen-activated protein
al., 2001).
kinase) pathway, but rather results from abnormalities in the
Neurofibromas develop in most or all NF1 patients (Friedman
cAMP-mediated opening of the channel. Enlarged peripheral
and Birch, 1997). NF1 patients can have a few or thousands of
nerves in NF1 mutant flies result from Ras or non-Ras pathway
these benign peripheral nerve tumors. Discrete neurofibromas
defects (Yager et al., 2001). Neurofibromin is also a substrate of
can be associated with any peripheral nerve or with small nerve
PKA. Aberrant K ⫹ currents have also been described in SCs from
endings under the skin, typically appear during or after puberty,
MPNST cell lines and could be induced in normal human SCs by
and are prone to growth during pregnancy (Dugoff and Sujansky,
exposure to cAMP analogs (Fieber, 1998). PAKs (p21-activated
1996). In contrast, plexiform neurofibromas expand within the
kinases) have also been implicated in SC transformation (Tang et
perineurium and displace surrounding tissue. Plexiform neuroal., 1998). R-Ras and R-Ras2/TC21 may mediate some effects of
fibromas are associated with major nerve trunks and appear in
Nf1 loss in SCs (Huang et al., 2004).
young children (for review, see Wiestler et al., 1994). Currently,
It seems reasonable that Nf1 mutant SCs would reveal deregthe only therapy for neurofibromas is surgical removal.
ulation of molecules necessary for normal neuron– glial interacRecent data strongly support the view that Schwann cells are a
tion and provide therapeutic targets for NF1 patients. To study
crucial pathogenic cell type in neurofibroma formation. Neuroneurofibroma formation resulting from Nf1 mutation, mice with
fibroma SCs aberrantly stimulate angiogenesis and are invasive
a targeted mutation in Nf1 were developed (Brannan et al., 1994;
(Sheela et al., 1990), and mutations in both Nf1 alleles are present
Jacks et al., 1994). Nf1 ⫺/⫺ mouse embryos die by E14.5, and adult
in neurofibroma SCs but not neurofibroma fibroblasts (Kluwe et
Nf1 ⫹/⫺ mice do not spontaneously develop neurofibromas.
al., 1999; Serra et al., 2001). A conditional (cre/lox) allele of Nf1
However, neurofibromas formed when Nf1 ⫺/⫺ embryonic stem
was used to ablate Nf1 in the SC lineage. These mice developed
cells
were added to wild-type blastocysts (Cichowski et al., 1999)
peripheral nerve tumors, but only when all the cells in the mice
or after wounding of Nf1 ⫹/⫺ peripheral nerves (Rizvi et al.,
were also Nf1 ⫹/⫺ (Zhu et al., 2002), suggesting a role for a permissive
2002). Moreover, when dorsal root ganglion cells are purified
haploinsufficient environment in conjunction with mutant SCs.
from Nf1 mutant embryos at E12.5, the Nf1 ⫹/⫺ and Nf1 ⫺/⫺
NF1 encodes a GTPase activating protein for Ras proteins
Schwann
cells from these cultures do show some abnormalities.
called neurofibromin (for review, see Donovan et al., 2002).
Notably, an additional morphologically transformed, fastThus, loss of neurofibromin through mutation at the Nf1 locus
growing, p75NGFR, S100␤, and GFAP-expressing subpopulamight be expected to result in a failure to terminate Ras signals.
tion of cells, denoted Nf1 ⫺/⫺ TXF, is also present in these cultures
Indeed, increased levels of Ras-GTP are detected in SCs isolated
(Kim et al., 1997; Rizvi et al., 2002). These cells have been used as
from neurofibromas (Sherman et al., 2000). Ras-GTP is also elea model of neurofibroma formation.
vated in SCs hemizygous or null at Nf1 using a biochemical assay
Corfas et al. • Axon–Schwann Cell Interactions
Recently, studies using the candidate gene approach and more
global gene expression profiling have provided new insights into
neurofibroma formation. As an example of the candidate gene
approach, Ratner and colleagues found that Nf1 ⫺/⫺ TXF cells
aberrantly express the epidermal growth factor receptor (EGFR)
(DeClue et al., 2000). Supporting use of the Nf1 ⫺/⫺ TXF cells as a
model for tumorigenesis, EGFR is also aberrantly expressed in a
subset of S100␤-expressing cells in neurofibromas and in mouse
and human MPNST cell lines, in which EGFR antagonists inhibit
cell growth (DeClue et al., 2000; Li et al., 2002). This has led to an
ongoing therapeutic trial of EGFR antagonists in MPNST.
Applying global gene expression profiling to the Nf1 mutant
mice has revealed numerous new candidate genes. For example,
cDNA microarray analysis showed that expression of Blbp (brain
lipid binding protein)/Fabp7 (fatty acid binding protein) was increased in Nf1 ⫺/⫺ TXF cells (Miller et al., 2003). The correlation
between the higher expression levels of BLBP, which has been
shown to mediate adhesion between neurons and glia (Feng et al.,
1994), and the defects in the ability of Nf1 ⫺/⫺ TXF Schwann cells
to extend processes along axons suggested that these events could
be related (Miller et al., 2003). Strikingly, BLBP blocking antibodies enabled process outgrowth from Nf1 ⫺/⫺ TXF cells and
restored interaction with axons (Miller et al., 2003). BLBP expression was also detected in EGFR-positive cell lines derived
from human MPNST and Nf1:p53 double-mutant mice (Li et al.,
2002). Thus, these results not only validate the utility of the
Nf1 ⫺/⫺ TXF system to identify genes relevant to tumorigenesis
but implicate BLBP in the disease phenotype.
In summary, peripheral nerve tumors that form in neurofibromatosis type 1 disrupt axon–SC interactions and peripheral
nerve structure. Currently available knock-out mice and SC culture models are available to study peripheral nerve tumorigenesis, and insights into the involvement of Ras signaling, proteins
including BLBP, and tyrosine kinase pathways driven by EGFR in
these tumors are providing targets for possible therapeutic interventions in NF1. Many important questions remain, including
the role of non-SCs in neurofibromas, identification of additional proteins that are biomarkers or therapeutic targets in disease, and identification of the pathway by which loss of NF1
disrupts axon– glial interactions.
References
Altevogt BM, Kleopa KA, Postma FR, Scherer SS, Paul DL (2002) Connexin29 is uniquely distributed within myelinating glial cells of the central
and peripheral nervous systems. J Neurosci 22:6458 – 6470.
Apostolski S, Sadiq SA, Hays A, Corbo M, Suturkova-Milosevic L, Chaliff P,
Stefansson K, LeBaron RG, Ruoslahti E, Hays AP, Latov N (1994) Identification of Gal(beta 1–3)GalNAc bearing glycoproteins at the nodes of
Ranvier in peripheral nerve. J Neurosci Res 38:134 –141.
Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses:
glia, the unacknowledged partner. Trends Neurosci 22:208 –215.
Astrow SH, Qiang H, Ko CP (1998) Perisynaptic Schwann cells at neuromuscular junctions revealed by a novel monoclonal antibody. J Neurocytol 27:667– 681.
Auld DS, Colomar A, Belair EL, Castonguay A, Pinard A, Rousse I, Thomas S,
Robitaille R (2003) Modulation of neurotransmission by reciprocal
synapse-glial interactions at the neuromuscular junction. J Neurocytol
32:1003–1015.
Berghs S, Aggujaro D, Dirkx Jr R, Maksimova E, Stabach P, Hermel JM,
Zhang JP, Philbrick W, Slepnev V, Ort T, Solimena M (2000) betaIV
spectrin, a new spectrin localized at axon initial segments and nodes of
ranvier in the central and peripheral nervous system. J Cell Biol
151:985–1002.
Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St. Martin M, Li J,
Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ (2001) Axon-
J. Neurosci., October 20, 2004 • 24(42):9250 –9260 • 9257
glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin. Neuron 30:369 –383.
Birks R, Katz B, Miledi R (1960) Physiological and structural changes at the
amphibian myoneural junction, in the course of nerve degeneration.
J Physiol (Lond) 150:145–168.
Boyle ME, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B (2001)
Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30:385–397.
Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG (1994) Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev
8:1019 –1029.
Cao G, Ko CP (2001) Schwann cell-conditioned medium modulates synaptic activities at Xenopus neuromuscular junctions in vitro. Soc Neurosci
Abstr 27:711.12.
Castonguay A, Robitaille R (2001) Differential regulation of transmitter release by presynaptic and glial Ca 2⫹ internal stores at the neuromuscular
synapse. J Neurosci 21:1911–1922.
Chandross KJ, Spray DC, Cohen RI, Kumar NM, Kremer M, Dermietzel R,
Kessler JA (1996) TNF alpha inhibits Schwann cell proliferation, connexin46 expression, and gap junctional communication. Mol Cell Neurosci 7:479 –500.
Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, DenisenkoNehrbass N, Guennoc AM, Girault JA, Brophy PJ, Lubetzki C (2002)
Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal
complex at the axoglial junction. Curr Biol 12:217–220.
Chen L, Ko CP (1994) Extension of synaptic extracellular matrix during
nerve terminal sprouting in living frog neuromuscular junctions. J Neurosci 14:796 – 808.
Chen LL, Folsom DB, Ko CP (1991) The remodeling of synaptic extracellular matrix and its dynamic relationship with nerve terminals at living frog
neuromuscular junctions. J Neurosci 11:2920 –2930.
Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G (2003)
Disruption of ErbB receptor signaling in adult non-myelinating Schwann
cells causes progressive sensory loss. Nat Neurosci 6:1186 –1193.
Ching W, Zanazzi G, Levinson SR, Salzer JL (1999) Clustering of neuronal
sodium channels requires contact with myelinating Schwann cells. J Neurocytol 28:295–301.
Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME,
Bronson RT, Jacks T (1999) Mouse models of tumor development in
neurofibromatosis type 1. Science 286:2172–2176.
Corfas G, Rosen KM, Aratake H, Krauss R, Fischbach GD (1995) Differential expression of ARIA isoforms in the rat brain. Neuron 14:103–115.
Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor
p75NTR as a positive modulator of myelination. Science 298:1245–1248.
Cravioto H (1969) The ultrastructure of acoustic nerve tumors. Acta Neuropathol (Berl) 12:116 –140.
Custer AW, Kazarinova-Noyes K, Sakurai T, Xu X, Simon W, Grumet M,
Shrager P (2003) The role of the ankyrin-binding protein NrCAM in
node of Ranvier formation. J Neurosci 23:10032–10039.
Davis JQ, Lambert S, Bennett V (1996) Molecular composition of the node
of Ranvier: identification of ankyrin-binding cell adhesion molecules
neurofascin (mucin⫹/third FNIII domain-) and NrCAM at nodal axon
segments. J Cell Biol 135:1355–1367.
DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC,
Viskochil D, Ratner N (2000) Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models.
J Clin Invest 105:1233–1241.
Devaux JJ, Kleopa KA, Cooper EC, Scherer SS (2004) KCNQ2 is a nodal K ⫹
channel. J Neurosci 24:1236 –1244.
Dong Z, Brennan A, Liu N, Yarden Y, Lefkowitz G, Mirsky R, Jessen KR
(1995) Neu differentiation factor is a neuron-glia signal and regulates
survival, proliferation, and maturation of rat Schwann cell precursors.
Neuron 15:585–596.
Donovan S, Shannon KM, Bollag G (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta
1602:23– 45.
Dugoff L, Sujansky E (1996) Neurofibromatosis type 1 and pregnancy. Am J
Med Genet 66:7–10.
Dupree JL, Girault JA, Popko B (1999) Axo-glial interactions regulate the
localization of axonal paranodal proteins. J Cell Biol 147:1145–1152.
9258 • J. Neurosci., October 20, 2004 • 24(42):9250 –9260
Einheber S, Zanazzi G, Ching W, Scherer S, Milner TA, Peles E, Salzer JL
(1997) The axonal membrane protein Caspr, a homologue of neurexin
IV, is a component of the septate-like paranodal junctions that assemble
during myelination. J Cell Biol 139:1495–1506.
Erickson SL, O’Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M, Lu LH,
Moore MW (1997) ErbB3 is required for normal cerebellar and cardiac
development: a comparison with ErbB2-and heregulin-deficient mice.
Development 124:4999 –5011.
Erlandson RA, Woodruff JM (1982) Peripheral nerve sheath tumors: an
electron microscopic study of 43 cases. Cancer 49:273–287.
Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002)
Malignant peripheral nerve sheath tumours in neurofibromatosis 1.
J Med Genet 39:311–314.
Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kucukceylan N,
Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S,
Nurnberg P (2000) Minor lesion mutational spectrum of the entire NF1
gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet
66:790 – 818.
Faissner A, Kruse J, Nieke J, Schachner M (1984) Expression of neural cell
adhesion molecule L1 during development, in neurological mutants and
in the peripheral nervous system. Brain Res 317:69 – 82.
Feltri ML, Graus Porta D, Previtali SC, Nodari A, Migliavacca B, Cassetti A,
Littlewood-Evans A, Reichardt LF, Messing A, Quattrini A, Mueller U,
Wrabetz L (2002) Conditional disruption of beta 1 integrin in Schwann
cells impedes interactions with axons. J Cell Biol 156:199 –209.
Feng Z, Ko CP (2004) Transforming growth factor (TGF)-beta 1 mediates
Schwann cell-induced synaptogenesis at the neuromuscular junction in
vitro. Soc Neurosci Abstr 30:385:18.
Feng L, Hatten ME, Heintz N (1994) Brain lipid-binding protein (BLBP): a
novel signaling system in the developing mammalian CNS. Neuron
12:895–908.
Fieber LA (1998) Ionic currents in normal and neurofibromatosis type
1-affected human Schwann cells: induction of tumor cell K current in
normal Schwann cells by cyclic AMP. J Neurosci Res 54:495–506.
Friedman JM, Birch PH (1997) Type 1 neurofibromatosis: a descriptive
analysis of the disorder in 1,728 patients. Am J Med Genet 70:138 –143.
Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C (2000) A
dual role of erbB2 in myelination and in expansion of the schwann cell
precursor pool. J Cell Biol 148:1035–1046.
Garver TD, Ren Q, Tuvia S, Bennett V (1997) Tyrosine phosphorylation at a
site highly conserved in the L1 family of cell adhesion molecules abolishes
ankyrin binding and increases lateral mobility of neurofascin. J Cell Biol
137:703–714.
Gollan L, Sabanay H, Poliak S, Berglund EO, Ranscht B, Peles E (2002)
Retention of a cell adhesion complex at the paranodal junction requires
the cytoplasmic region of Caspr. J Cell Biol 157:1247–1256.
Gollan L, Salomon D, Salzer JL, Peles E (2003) Caspr regulates the processing of contactin and inhibits its binding to neurofascin. J Cell Biol
163:1213–1218.
Goutebroze L, Carnaud M, Denisenko N, Boutterin MC, Girault JA (2003)
Syndecan-3 and syndecan-4 are enriched in Schwann cell perinodal processes. BMC Neurosci 4:29.
Guenard V, Gwynn LA, Wood PM (1995) Transforming growth factor-beta
blocks myelination but not ensheathment of axons by Schwann cells in
vitro. J Neurosci 15:419 – 428.
Guo HF, The I, Hannan F, Bernards A, Zhong Y (1997) Requirement of
Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276:795–798.
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
JAMA 278:51–57.
Hsieh ST, Kidd GJ, Crawford TO, Xu Z, Lin WM, Trapp BD, Cleveland DW,
Griffin JW (1994) Regional modulation of neurofilament organization
by myelination in normal axons. J Neurosci 14:6392– 6401.
Huang Y, Rangwala F, Fulkerson PC, Ling B, Reed E, Cox AD, Kamholz J,
Ratner N (2004) Role of TC21/R-Ras2 in enhanced migration of
neurofibromin-deficient Schwann cells. Oncogene 23:368 –378.
Ishibashi T, Dupree JL, Ikenaka K, Hirahara Y, Honke K, Peles E, Popko B,
Suzuki K, Nishino H, Baba H (2002) A myelin galactolipid, sulfatide, is
Corfas et al. • Axon–Schwann Cell Interactions
essential for maintenance of ion channels on myelinated axon but not
essential for initial cluster formation. J Neurosci 22:6507– 6514.
Isom LL (2002) The role of sodium channels in cell adhesion. Front Biosci
7:12–23.
Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA (1994)
Tumour predisposition in mice heterozygous for a targeted mutation in
Nf1. Nat Genet 7:353–361.
Jahromi BS, Robitaille R, Charlton MP (1992) Transmitter release increases
intracellular calcium in perisynaptic Schwann cells in situ. Neuron
8:1069 –1077.
Jenkins SM, Bennett V (2002) Developing nodes of Ranvier are defined by
ankyrin-G clustering and are independent of paranodal axoglial adhesion.
Proc Natl Acad Sci USA 99:2303–2308.
Jessen KR, Mirsky R (1999) Schwann cells and their precursors emerge as
major regulators of nerve development. Trends Neurosci 22:402– 410.
Jessen KR, Morgan L, Stewart HJ, Mirsky R (1990) Three markers of adult
non-myelin-forming Schwann cells, 217c(Ran-1), A5E3 and GFAP: development and regulation by neuron-Schwann cell interactions. Development 109:91–103.
Jessen KR, Brennan A, Morgan L, Mirsky R, Kent A, Hashimoto Y, Gavrilovic
J (1994) The Schwann cell precursor and its fate: a study of cell death and
differentiation during gliogenesis in rat embryonic nerves. Neuron
12:509 –527.
Johnson MD, Glick AD, Davis BW (1988) Immunohistochemical evaluation of Leu-7, myelin basic-protein, S100-protein, glial-fibrillary acidicprotein, and LN3 immunoreactivity in nerve sheath tumors and sarcomas. Arch Pathol Lab Med 112:155–160.
Kang H, Tian L, Thompson W (2003) Terminal Schwann cells guide the
reinnervation of muscle after nerve injury. J Neurocytol 32:975–985.
Kayl AE, Moore III BD (2000) Behavioral phenotype of neurofibromatosis,
type 1. Ment Retard Dev Disabil Res Rev 6:117–124.
Kim HA, Rosenbaum T, Marchionni MA, Ratner N, DeClue JE (1995)
Schwann cells from neurofibromin deficient mice exhibit activation of
p21ras, inhibition of cell proliferation and morphological changes. Oncogene 11:325–335.
Kim HA, Ling B, Ratner N (1997) Nf1-deficient mouse Schwann cells are
angiogenic and invasive and can be induced to hyperproliferate: reversion
of some phenotypes by an inhibitor of farnesyl protein transferase. Mol
Cell Biol 17:862– 872.
Kluwe L, Friedrich R, Mautner VF (1999) Loss of NF1 allele in Schwann cells
but not in fibroblasts derived from an NF1-associated neurofibroma.
Genes Chromosomes Cancer 24:283–285.
Ko CP (1987) A lectin, peanut agglutinin, as a probe for the extracellular
matrix in living neuromuscular junctions. J Neurocytol 16:567–576.
Ko CP, Chen L (1996) Synaptic remodeling revealed by repeated in vivo
observations and electron microscopy of identified frog neuromuscular
junctions. J Neurosci 16:1780 –1790.
Koirala S, Qiang H, Ko CP (2000) Reciprocal interactions between perisynaptic Schwann cells and regenerating nerve terminals at the frog neuromuscular junction. J Neurobiol 44:343–360.
Koirala S, Reddy LV, Ko CP (2003) Roles of glial cells in the formation,
function, and maintenance of the neuromuscular junction. J Neurocytol
32:987–1002.
Kordeli E, Lambert S, Bennett V (1995) AnkyrinG. A new ankyrin gene with
neural-specific isoforms localized at the axonal initial segment and node
of Ranvier. J Biol Chem 270:2352–2359.
Kramer R, Bucay N, Kane DJ, Martin LE, Tarpley JE, Theill LE (1996) Neuregulins with an Ig-like domain are essential for mouse myocardial and
neuronal development. Proc Natl Acad Sci USA 93:4833– 4838.
Kullberg RW, Lentz TL, Cohen MW (1977) Development of the myotomal
neuromuscular junction in Xenopus laevis: an electrophysiological and
fine-structural study. Dev Biol 60:101–129.
Lambert S, Davis JQ, Bennett V (1997) Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define
early developmental intermediates. J Neurosci 17:7025–7036.
Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development.
Nature 378:394 –398.
Legius E, Marchuk DA, Collins FS, Glover TW (1993) Somatic deletion of
the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a
tumour suppressor gene hypothesis. Nat Genet 3:122–126.
Li H, Velasco-Miguel S, Vass WC, Parada LF, DeClue JE (2002) Epidermal
Corfas et al. • Axon–Schwann Cell Interactions
growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. Cancer Res 62:4507– 4513.
Lin W, Sanchez HB, Deerinck T, Morris JK, Ellisman M, Lee KF (2000)
Aberrant development of motor axons and neuromuscular synapses in
erbB2-deficient mice. Proc Natl Acad Sci USA 97:1299 –1304.
Lopez-Correa C, Dorschner M, Brems H, Lazaro C, Clementi M, Upadhyaya
M, Dooijes D, Moog U, Kehrer-Sawatzki H, Rutkowski JL, Fryns JP,
Marynen P, Stephens K, Legius E (2001) Recombination hotspot in NF1
microdeletion patients. Hum Mol Genet 10:1387–1392.
Lustig M, Zanazzi G, Sakurai T, Blanco C, Levinson SR, Lambert S, Grumet
M, Salzer JL (2001) Nr-CAM and neurofascin interactions regulate
ankyrin G and sodium channel clustering at the node of Ranvier. Curr
Biol 11:1864 –1869.
Macleod GT, Dickens PA, Bennett MR (2001) Formation and function of
synapses with respect to Schwann cells at the end of motor nerve terminal
branches on mature amphibian (Bufo marinus) muscle. J Neurosci
21:2380 –2392.
Mahanthappa NK, Anton ES, Matthew WD (1996) Glial growth factor 2, a
soluble neuregulin, directly increases Schwann cell motility and indirectly
promotes neurite outgrowth. J Neurosci 16:4673– 4683.
Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk
C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, Wroblewski D, Lynch C, Baldassare M, Hiles I, Davis JB, Hsuan J, Totty MF,
Otsu M, McBurney RN, Waterfield MD, et al. (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:312–318.
Martini R, Schachner M, Faissner A (1990) Enhanced expression of the extracellular matrix molecule J1/tenascin in the regenerating adult mouse
sciatic nerve. J Neurocytol 19:601– 616.
Melendez-Vasquez CV, Rios JC, Zanazzi G, Lambert S, Bretscher A, Salzer JL
(2001) Nodes of Ranvier form in association with ezrin-radixin-moesin
(ERM)-positive Schwann cell processes. Proc Natl Acad Sci USA
98:1235–1240.
Menegoz M, Gaspar P, Le Bert M, Galvez T, Burgaya F, Palfrey C, Ezan P,
Arnos F, Girault JA (1997) Paranodin, a glycoprotein of neuronal paranodal membranes. Neuron 19:319 –331.
Meyer D, Birchmeier C (1995) Multiple essential functions of neuregulin in
development. Nature 378:386 –390.
Meyer D, Yamaai T, Garratt A, Riethmacher-Sonnenberg E, Kane D, Theill
LE, Birchmeier C (1997) Isoform-specific expression and function of
neuregulin. Development 124:3575–3586.
Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier
C, Role L, Lai C, Schwab MH, Nave KA (2004) Axonal neuregulin-1
regulates myelin sheath thickness. Science 304:700 –703.
Miller SJ, Li H, Rizvi TA, Huang Y, Johansson G, Bowersock J, Sidani A,
Vitullo J, Vogel K, Parysek LM, DeClue JE, Ratner N (2003) Brain lipid
binding protein in axon-Schwann cell interactions and peripheral nerve
tumorigenesis. Mol Cell Biol 23:2213–2224.
Morris JK, Lin W, Hauser C, Marchuk Y, Getman D, Lee KF (1999) Rescue
of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2
in peripheral nervous system development. Neuron 23:273–283.
Newman EA, Volterra A (2004) Glial control of synaptic function. Glia
47:207–208.
O’Malley JP, Waran MT, Balice-Gordon RJ (1999) In vivo observations of
terminal Schwann cells at normal, denervated, and reinnervated mouse
neuromuscular junctions. J Neurobiol 38:270 –286.
Pedraza L, Huang JK, Colman DR (2001) Organizing principles of the axoglial apparatus. Neuron 30:335–344.
Peles E, Nativ M, Lustig M, Grumet M, Schilling J, Martinez R, Plowman GD,
Schlessinger J (1997) Identification of a novel contactin-associated
transmembrane receptor with multiple domains implicated in proteinprotein interactions. EMBO J 16:978 –988.
Peltonen J, Jaakkola S, Lebwohl M, Renvall S, Risteli L, Virtanen I, Uitto J
(1988) Cellular differentiation and expression of matrix genes in type 1
neurofibromatosis. Lab Invest 59:760 –771.
Peng HB, Yang JF, Dai Z, Lee CW, Hung HW, Feng ZH, Ko CP (2003)
Differential effects of neurotrophins and schwann cell-derived signals on
neuronal survival/growth and synaptogenesis. J Neurosci 23:5050 –5060.
Poliak S, Peles E (2003) The local differentiation of myelinated axons at
nodes of Ranvier. Nat Rev Neurosci 4:968 –980.
Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, Trimmer JS,
Shrager P, Peles E (1999) Caspr2, a new member of the neurexin super-
J. Neurosci., October 20, 2004 • 24(42):9250 –9260 • 9259
family, is localized at the juxtaparanodes of myelinated axons and associates with K ⫹ channels. Neuron 24:1037–1047.
Poliak S, Gollan L, Salomon D, Berglund EO, Ohara R, Ranscht B, Peles E
(2001) Localization of Caspr2 in myelinated nerves depends on axon–
glia interactions and the generation of barriers along the axon. J Neurosci
21:7568 –7575.
Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart
CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E (2003) Juxtaparanodal
clustering of Shaker-like K ⫹ channels in myelinated axons depends on
Caspr2 and TAG-1. J Cell Biol 162:1149 –1160.
Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1.
Am J Epidemiol 151:33– 40.
Reddy LV, Koirala S, Sugiura Y, Herrera AA, Ko CP (2003) Glial cells maintain synaptic structure and function and promote development of the
neuromuscular junction in vivo. Neuron 40:563–580.
Reist NE, Smith SJ (1992) Neurally evoked calcium transients in terminal
Schwann cells at the neuromuscular junction. Proc Natl Acad Sci USA
89:7625–7629.
Reynolds ML, Woolf CJ (1992) Terminal Schwann cells elaborate extensive
processes following denervation of the motor endplate. J Neurocytol
21:50 – 66.
Ridley AJ, Paterson HF, Noble M, Land H (1988) Ras-mediated cell cycle
arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J 7:1635–1645.
Rieger F, Daniloff JK, Pincon-Raymond M, Crossin KL, Grumet M, Edelman
GM (1986) Neuronal cell adhesion molecules and cytotactin are colocalized at the node of Ranvier. J Cell Biol 103:379 –391.
Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin
GR, Birchmeier C (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725–730.
Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly
J, Peles E, Salzer JL (2000) Contactin-associated protein (Caspr) and
contactin form a complex that is targeted to the paranodal junctions
during myelination. J Neurosci 20:8354 – 8364.
Rizvi TA, Huang Y, Sidani A, Atit R, Largaespada DA, Boissy RE, Ratner N
(2002) A novel cytokine pathway suppresses glial cell melanogenesis after
injury to adult nerve. J Neurosci 22:9831–9840.
Robitaille R (1998) Modulation of synaptic efficacy and synaptic depression
by glial cells at the frog neuromuscular junction. Neuron 21:847– 855.
Saito F, Moore SA, Barresi R, Henry MD, Messing A, Ross-Barta SE, Cohn
RD, Williamson RA, Sluka KA, Sherman DL, Brophy PJ, Schmelzer JD,
Low PA, Wrabetz L, Feltri ML, Campbell KP (2003) Unique role of
dystroglycan in peripheral nerve myelination, nodal structure, and sodium channel stabilization. Neuron 38:747–758.
Salzer JL (2003) Polarized domains of myelinated axons. Neuron
40:297–318.
Scherer SS, Xu T, Crino P, Arroyo EJ, Gutmann DH (2001) Ezrin, radixin,
and moesin are components of Schwann cell microvilli. J Neurosci Res
65:150 –164.
Serra E, Rosenbaum T, Nadal M, Winner U, Ars E, Estivill X, Lazaro C (2001)
Mitotic recombination effects homozygosity for NF1 germline mutations
in neurofibromas. Nat Genet 28:294 –296.
Shah NM, Marchionni MA, Isaacs I, Stroobant P, Anderson DJ (1994) Glial
growth factor restricts mammalian neural crest stem cells to a glial fate.
Cell 77:349 –360.
Sheela S, Riccardi VM, Ratner N (1990) Angiogenic and invasive properties
of neurofibroma Schwann cells. J Cell Biol 111:645– 653.
Sherman LS, Atit R, Rosenbaum T, Cox AD, Ratner N (2000) Single cell
Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem
275:30740 –30745.
Son YJ, Thompson WJ (1995) Nerve sprouting in muscle is induced and
guided by processes extended by Schwann cells. Neuron 14:133–141.
Srinivasan Y, Elmer L, Davis J, Bennett V, Angelides K (1988) Ankyrin and
spectrin associate with voltage-dependent sodium channels in brain. Nature 333:177–180.
Stefansson K, Wollmann R, Jerkovic M (1982) S-100 protein in soft-tissue
tumors derived from Schwann cells and melanocytes. Am J Pathol
106:261–268.
Syroid DE, Maycox PR, Burrola PG, Liu N, Wen D, Lee KF, Lemke G, Kilpatrick TJ (1996) Cell death in the Schwann cell lineage and its regulation by neuregulin. Proc Natl Acad Sci USA 93:9229 –9234.
9260 • J. Neurosci., October 20, 2004 • 24(42):9250 –9260
Syroid DE, Zorick TS, Arbet-Engels C, Kilpatrick TJ, Eckhart W, Lemke G
(1999) A role for insulin-like growth factor-I in the regulation of
Schwann cell survival. J Neurosci 19:2059 –2068.
Tait S, Gunn-Moore F, Collinson JM, Huang J, Lubetzki C, Pedraza L, Sherman DL, Colman DR, Brophy PJ (2000) An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction.
J Cell Biol 150:657– 666.
Tang Y, Marwaha S, Rutkowski JL, Tennekoon GI, Phillips PC, Field J (1998)
A role for Pak protein kinases in Schwann cell transformation. Proc Natl
Acad Sci USA 95:5139 –5144.
Trachtenberg JT, Thompson WJ (1996) Schwann cell apoptosis at developing neuromuscular junctions is regulated by glial growth factor. Nature
379:174 –177.
Trachtenberg JT, Thompson WJ (1997) Nerve terminal withdrawal from
rat neuromuscular junctions induced by neuregulin and Schwann cells.
J Neurosci 17:6243– 6255.
Traka M, Dupree JL, Popko B, Karagogeos D (2002) The neuronal adhesion
protein TAG-1 is expressed by Schwann cells and oligodendrocytes and is
localized to the juxtaparanodal region of myelinated fibers. J Neurosci
22:3016 –3024.
Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y,
Fukamauchi F, Watanabe K, Soliven B, Girault JA, Karagogeos D (2003)
Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol
162:1161–1172.
Ullian EM, Christopherson KS, Barres BA (2004) Role for glia in synaptogenesis. Glia 47:209 –216.
Vabnick I, Novakovic SD, Levinson SR, Schachner M, Shrager P (1996) The
clustering of axonal sodium channels during development of the peripheral nervous system. J Neurosci 16:4914 – 4922.
Vabnick I, Trimmer JS, Schwarz TL, Levinson SR, Risal D, Shrager P (1999)
Dynamic potassium channel distributions during axonal development
prevent aberrant firing patterns. J Neurosci 19:747–758.
Corfas et al. • Axon–Schwann Cell Interactions
Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL (1993)
Heteromultimeric K ⫹ channels in terminal and juxtaparanodal regions
of neurons. Nature 365:75–79.
Wiestler OD, Brustle O, Eibl RH, Radner H, Aguzzi A, Kleihues P (1994)
Oncogene transfer into the brain. Recent Results Cancer Res 135:55– 66.
Wilson GF, Chiu SY (1993) Mitogenic factors regulate ion channels in
Schwann cells cultured from newborn rat sciatic nerve. J Physiol (Lond)
470:501–520.
Woldeyesus MT, Britsch S, Riethmacher D, Xu L, Sonnenberg-Riethmacher
E, Abou-Rebyeh F, Harvey R, Caroni P, Birchmeier C (1999) Peripheral
nervous system defects in erbB2 mutants following genetic rescue of heart
development. Genes Dev 13:2538 –2548.
Wolpowitz D, Mason TB, Dietrich P, Mendelsohn M, Talmage DA, Role LW
(2000) Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 25:79 –91.
Woolf CJ, Reynolds ML, Chong MS, Emson P, Irwin N, Benowitz LI (1992)
Denervation of the motor endplate results in the rapid expression by
terminal Schwann cells of the growth-associated protein GAP-43. J Neurosci 12:3999 – 4010.
Yager J, Richards S, Hekmat-Scafe DS, Hurd DD, Sundaresan V, Caprette DR,
Saxton WM, Carlson JR, Stern M (2001) Control of Drosophila perineurial glial growth by interacting neurotransmitter-mediated signaling
pathways. Proc Natl Acad Sci USA 98:10445–10450.
Yang JF, Cao G, Koirala S, Reddy LV, Ko CP (2001) Schwann cells express
active agrin and enhance aggregation of acetylcholine receptors on muscle
fibers. J Neurosci 21:9572–9584.
Yin X, Crawford TO, Griffin JW, Tu P, Lee VM, Li C, Roder J, Trapp BD
(1998) Myelin-associated glycoprotein is a myelin signal that modulates
the caliber of myelinated axons. J Neurosci 18:1953–1962.
Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF (2002) Neurofibromas in
NF1: Schwann cell origin and role of tumor environment. Science 296:
920 –922.